The following abbreviations are used throughout the present specification:                GAG: glycosaminoglycan        KS: keratan sulfate        HS: heparan sulfate        CS: chondroitin sulfate        CS-4S: chondroitin-4-sulfate        CS-6S: chondroitin-6-sulfate        DS: dermatan sulfate (also called chondroitin sulfate B)        GSD I: glycogen storage disease type 1        GSD II: glycogen storage disease type 2 (Pompe disease)        Hep: heparin        HA: hyaluronic acid        LIPO: lipofuscinoses        MPS: mucopolysaccharidoses        ML: mucolipidoses        MLD: metachromatic leukodystrophy        NP: Niemann-Pick diseases        TS: Tay-Sachs disease        
Lysosomal storage diseases are diseases caused by abnormality of enzymes present in lysosomes.
Mucopolysaccharidoses are kinds of lysosomal storage diseases and form a class of hereditary diseases caused by deficiency of enzymes (lowered activity of enzymes) involved in degradation metabolism of GAGs. In accordance with the species of the defective enzyme, GAG of a specific species is known to be accumulated in tissues and excreted into body fluids. Clinical manifestations of mucopolysaccharidoses are diversified, but most cases involve coarse facial expression, dysostosis multiplex, and visceromegaly. In some cases, hypacusia, cardiovascular disorders, and mental retardation are also observed.
Table 1-1 shows the known relations between types of mucopolysaccharidoses and corresponding GAGs that are accumulated (see, for example, “The Metabolic and Molecular Bases of Inherited Disease”, 7th edn., Scriver C R, Beaudet A L, Sly W S, Valle D (eds.), 1995, McGraw-Hill, New York).
TABLE 1-1mucopolysaccharidosesTypeDisease NameEnzyme DeficiencySubstance StoredI HHurler Syndromeα-L-iduronidaseHS, DSI SScheie Syndromesame as aboveHS, DSI H/SHurler-Scheie Complexsame as aboveHS, DSII AHunter Syndrome (Severe)iduronate sulfataseHS, DSII BHunter Syndrome (Mild)same as aboveHS, DSIII ASanfilippo Syndrome Aheparan N-sulfataseHSIII BSanfilippo Syndrome Bα-N-acetylglucosaminidaseHSIII CSanfilippo Syndrome Cacetyl CoA:α-glucosaminide N-HSacetyltransferaseIII DSanfilippo Syndrome DN-acetylglucosamine-6-sulfataseHSIV AMorquio Syndrome Agalactosamine-6-sulfataseKSIV BMorquio Syndrome Bβ-galactosidaseKSVI AMaroteaux-Lamy Syndromearylsulfatase BDS(Severe)VI BMaroteaux-Lamy Syndromesame as aboveDS(Mild)VIIβ-glucuronidase deficiencyβ-glucuronidaseHS, DS, CS-4S, CS-6S
TABLE 1-2mucolipidosesTypeDisease NameEnzyme DeficiencySubstance StoredIII-Cell diseaseN-acetylglucosamine-1-Inclusion bodyphosphotransferaseIIIPseudo-Hurlersame as above (Mild)Inclusion bodyPolydystrophy
However, until the present invention, it has remained unknown that each case of the mentioned mucopolysaccharidoses not only involves excretion in body fluids of the GAG species shown in Table 1-1, but also involves excretion in body fluids of large amounts of other species of GAGs.
Japanese Patent Application Laid-Open (kokai) No. 10-153600 discloses an assay method in which a solid phase to which a first receptor (anti-GAG antibodies such as anti-KS antibody, anti-CS antibody, anti-HS antibody or the like) is immobilized is brought into contact with a specimen containing a first ligand (GAG such as KS, CS, HS or the like), and formation of a complex between the first receptor and the first ligand is detected by a first-labeling-substance-labeled first receptor, to thereby assay the first ligand contained in the specimen. This publication also discloses that the method facilitates primary screening of GAG-related diseases (including mucopolysaccharidoses such as Morquio's syndrome and Hurler's syndrome).
However, Japanese Patent Application Laid-Open (kokai) No. 10-153600 neither discloses nor suggests that each case of the aforementioned mucopolysaccharidoses involves, in addition to the GAG species shown in Table 1-1 being excreted, excretion into body fluid of large amounts of other species of GAGs. Moreover, this publication neither discloses nor suggests whether measurement of GAG of a single species enables detection of all types of mucopolysaccharidoses, regardless of the classification (type) of mucopolysaccharidoses.
Mucolipidoses are also kinds of lysosomal storage diseases and are diseases that show similar clinical symptoms to those of mucopolysaccharidoses. It is known that types of the mucolipidoses are as shown in Table 1-2.
Also, GM1 gangliosidoses and fucosidosis are also kinds of lysosomal storage diseases. GM1 gangliosidoses are diseases in which GM1 ganglioside and β-galactose residue-containing oligosaccharides and glycoproteins are accumulated due to impediment in β-galactosidase, and fucosidosis are diseases in which oligosaccharides and glycoproteins having α-fucose residues are accumulated due to impediment in α-fucosidase.
In addition, galactosialidoses are also kinds of lysosomal storage diseases and are diseases in which sialyloligosaccharides and substances similar to the case of GM1 gangliosidoses are accumulated due to impediment in β-galactosidase and α-neuraminidase, and impediment in cathepsin A which is involved in the stabilization of these enzymes.
Furthermore, the following diseases are also kinds of lysosomal storage diseases.
Metachromatic leukodystrophy is a disease in which sulphatides are accumulated due to impediment in arylsulfatase A.
Niemann-Pick diseases are diseases in which sphingomyelin is accumulated. Niemann-Pick type B is due to impediment in acid sphingomyelinase, and Niemann-Pick type C is due to cholesterol esterification defect.
Tay-Sachs disease is disease in which GM2 ganglioside is accumulated due to impediment in α-subunit of N-acetyl-β-D-glucosaminidase A.
Sandhoff disease is disease in which GM2 ganglioside is accumulated due to impediment in β-subunit of N-acetyl-β-D-glucosaminidase A and B.
GM2 gangliosidoses are diseases in which GM2 ganglioside is accumulated due to impediment in GM2 activator protein.
Krabbe disease is disease in which galactocerebroside is accumulated due to impediment in β-D-galactocerebrosidase.
Fabry disease is disease in which globosides are accumulated due to impediment in α-D-galactosidase.
Gaucher diseases are diseases in which glucosylceramide is accumulated due to impediment in β-D-glucocerebrosidase.
Glycogen storage disease type 1 is disease in which glycogen is accumulated due to impediment in glucose-6-phosphatase.
Glycogen storage disease type 2 (also called Pompe disease) is disease in which glycogen is accumulated due to impediment in α-D-glucosidase.
Lipofuscinoses are caused by impediment in palmitoyl-protein thioesterase or tripeptidyl amino peptidase-I.
It has not been known that GAG is also discharged in a large amount into body fluids in these diseases.
Hereinafter, mucopolysaccharidoses, mucolipidoses, GM1 gangliosidoses, fucosidosis, galactosialidoses, metachromatic_leukodystrophy, Niemann-Pick diseases, Tay-Sachs disease, Sandhoff disease, GM2 gangliosidoses, Krabbe disease, Fabry disease, Gaucher diseases, glycogen storage diseases and lipofuscinoses are referred to as “mucopolysaccharidoses, etc.”
In general, mucopolysaccharidoses, etc. are asymptomatic in newborns, but onset thereof becomes clear by manifestations including arrested height gain, abnormal development of bones, and growth of shaggy hair during infancy or childhood. In some cases, although subjects are normal during neonatal periods, mental retardation gradually progresses over years. Therefore, diagnosis of mucopolysaccharidoses, etc. in an early newborn stage during which no clinical syndromes are manifested may possibly prevent mental retardation, etc., through early enzyme replacement therapy, genetic treatment, or bone marrow transplantation. Therefore, diagnosis of mucopolysaccharidoses, etc. is desirably performed for all newborns.
However, in Japan, for example, the number of newborns per year exceeds 1,000,000, and the frequency of onset of mucopolysaccharidoses, etc. is as low as one per 40,000 to 50,000, and since current diagnosis therefor, which detects deficiency or abnormality of enzymes, is cumbersome and expensive, demand exists for an accurate screening method to be performed before such an expensive diagnosis. In other words, if there can be provided a method for detecting patients suffering mucopolysaccharidoses, etc. with high accuracy, with high sensitivity, conveniently, quickly, and at low cost, without overlooking any patients of mucopolysaccharidoses, etc., presence or absence of mucopolysaccharidoses, etc. can be detected in all newborns, and thus precise, definite diagnosis of every patient of mucopolysaccharidoses, etc. can be attained at an early stage of the disease.